Intermediate for (R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-5-iodo-3-methyl-1-H-imidazo[1,2-a]imidazol-2-one

ABSTRACT

A novel process for the preparation of (R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-5-iodo-3-methyl-1-H-imidazo [1,2-α]imidazol-2-one (1):                    
     This compound is useful as an intermediate in the preparation of certain small molecules that are useful in the treatment or prevention of inflammatory and immune cell-mediated diseases. The present invention also relates to certain intermediates used in this novel process.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.09/918,915, filed on Jul. 31, 2001, which claims benefit to U.S.Provisional Application Ser. No. 60/224,166, filed on Aug. 9, 2000, bothof which are herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates generally to a novel process for thepreparation of(R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-5-iodo-3-methyl-1-H-imidazo[1,2-a]imidazol-2-one.This compound is useful as an intermediate in the preparation of certainsmall molecules that are useful in the treatment or prevention ofinflammatory and immune cell-mediated diseases. The present inventionalso relates to certain novel intermediates used in this novel process.

BACKGROUND OF THE INVENTION

(R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-5-iodo-3-methyl-1-H-imidazo[1,2-a]-imidazol-2-one(1) is an advanced intermediate used in the preparation of certain smallmolecules that inhibit the interaction of cellular adhesion molecules,specifically by antagonizing the binding of human intercellular adhesionmolecules (including ICAM-1, ICAM-2 and ICAM-3) to the Leukointegrins(especially CD18/CD11a or “LFA-1”). As a result, these small moleculesare useful in the treatment or prevention of inflammatory and immunecell-mediated diseases. See U.S. Nonprovisional application Ser. No.09/604,312 (Attorney Docket No. 9/162), Wu et al., filed on Jun. 27,2000, herein incorporated by reference.

The method that has been used to prepare compound 1 is illustrated inScheme 1 below.

In this procedure, an amino-ester 2 was reacted with3,5-dichlorophenylisothiocyanate 3 to provide thiohydantoin 4. To asolution of triphenylphosphine (PPh₃) was added the azide 5. Afterstirring at room temperature overnight, thiohydantoin 4 was added toprovide 6. Treatment of 6 with trifluoroacetic acid provided 7.Iodination was then carried out by reaction of 7 with N-iodosuccinimideand pyridinium p-toluenesulfonate to provide 1. Recovered 7 may berecycled to provide additional 1.

SUMMARY OF THE INVENTION

The present invention is directed to a novel process for the preparationof compound 1. A first aspect of the invention is directed to a processfor preparing a compound of the formula 1:

said process comprising the following steps:

a) reacting a compound of the formula I with a compound of the formula

 where R is C₁₋₆alkyl, in an aprotic organic solvent, followed by addinga triarylphosphine, a carbon tetrahalide and a tertiary amine, to form acompound of the formula IIa where R is C₁₋₆alkyl:

b) optionally hydrolyzing a compound of the formula IIa produced in stepa) by reacting the compound of formula IIa with a base to form acompound of the formula IIb:

c) reacting a compound of the formula IIa produced in step a) with aLewis acid and a phosphine oxide compound of the formula (R₁)₃PO,wherein R₁ is C₁₋₆alkyl or aryl, in an aprotic organic solvent to form acompound of the formula III:

 or

when the optional step b) is performed, reacting a compound of theformula IIb produced in step b) with a coupling agent in an aproticorganic solvent to form a compound of the formula III:

d) reacting a compound of the formula III produced in step c) with astrong base and a compound of the formula (R₂O)₂POCl, wherein R₂ isC₁₋₆alkyl or aryl, in a polar organic solvent at a temperature of about−90° C. to about 0° C. to form a compound of the formula IV where R₂ isC₁₋₆alkyl or aryl:

e) reacting a compound of the formula IV produced in step d) withtrimethylsilyl iodide, or with sodium iodide and trimethylsilylchloride, in an aprotic organic solvent to form a compound of theformula 1:

A second aspect of the invention is directed to the individual novelsteps of the above inventive process. A third aspect of the invention isdirected to the novel intermediates IIa, IIb, III and IV. A final aspectof the invention is directed to the novel urea intermediate of thefollowing formula Ia produced in the first step of the inventive processand its process of preparation:

wherein R is C₁₋₆alkyl.

DETAILED DESCRIPTION OF THE INVENTION

The individual steps of the inventive process are described in detailbelow, along with other aspects of the present invention.

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Forexample, a “C₁₋₆alkyl” is an alkyl group having from 1 to 6 carbonatoms, which group can be branched or unbranched. The term “aryl”,either alone or as part of another group, shall be understood to mean anoptionally substituted 6-10 membered aromatic carbocycle; “aryl”includes, for example, phenyl and naphthyl, each of which may beoptionally substituted.

Optimum reaction conditions and reaction times for the individual stepsmay vary depending on the particular reactants used. Unless otherwisespecified, solvents, temperatures, pressures and other reactionconditions may be readily selected by one of ordinary skill in the art.Specific procedures are provided in the Synthetic Examples section.Typically, reaction progress may be monitored by thin layerchromatography (TLC) if desired. Intermediates and products may bepurified by chromatography on silica gel and/or recrystallization.Unless otherwise set forth, the starting materials and reagents areeither commercially available or may be prepared by one skilled in theart using methods described in the chemical literature.

Step (a)

Step a) of the inventive process comprises reacting a compound of theformula I with a compound of the formula

where R is C₁₋₆alkyl, in an aprotic organic solvent, followed by addinga triarylphosphine, a carbon tetrahalide and a tertiary amine, to form acompound of the formula IIa where R is C₁₋₆alkyl:

The starting material of formula I is prepared as described in Yee, N.,“Self-Regeneration of Stereocenters: A Practical EnantiospecificSynthesis of LFA-1 Antagonist BIRT-377”, Org. Lett. 2000, 2, 2781-2783,which is herein incorporated by reference in its entirety. This processis set forth in detail below:

The commercially available (D)-N-Boc-alanine 9 is reacted with3,5-dichloroaniline via a mixed anhydride intermediate (i-BuOCOCl,N-methylmorpholine, −10° C. to rt, THF) to give amide 10. Deprotectionof the crude amide 10 by TFA in dichloromethane afforded amino N-arylamide 11 in 92% yield over two steps.

The amino amide 11 is treated with pivalaldehyde in refluxing pentane. Acrystalline solid is directly formed from the reaction mixture andidentified as the desired trans imidazolidinone 12 as a singlediastereomer in 74% yield. After protection of 12 (TFAA,

Et₃N, 0° C. to rt, CH₂Cl₂, 98% yield) to obtain 13, the crude 13 in THFis deprotonated with LiN(TMS)₂ at −30 to −20° C. and then the resultingenolate is alkylated at −30° C. to 0° C. with 4-bromobenzyl bromide fromthe opposite face of the t-butyl group to give the 5,5-disubstituted 14as a single diastereomer in 96% yield.

The trifluoroacetamide group of 14 is first hydrolyzed (1.5 eq.BnMe₃NOH, 2.0 eq. 50% NaOH, rt to 40° C., dioxane) to give a mixture ofthe corresponding partially hydrolyzed N-unsubstituted acetal of 14,Schiff base of I, and I itself. Subsequent direct addition of 6N HCl tothe above mixture resulted in complete hydrolysis to afford amino amideI in quantitative yield.

In step (a) of the present inventive process, the compound of formula Iis first reacted with an isocyanatoacetate of the formula

where R is C₁₋₆alkyl to form a urea of the following formula Ia in situ:

where R is C₁₋₆alkyl. It is not necessary to isolate the novel urea Ia,although it has been isolated and characterized. The urea of formula Iais dehydrated in situ by adding a triarylphosphine, a carbon tetrahalideand a tertiary amine to the reaction mixture. The resulting carbodiimideundergoes a spontaneous cyclization to provide the ester of formula IIain good yield.

The formation of ureas from isocyanates in general is documented in thescientific literature (See, e.g., Chem. Rev. 1981, 589, and referencescited therein). In the process of the present invention, however, it isnot necessary to isolate the urea, which can be dehydrated in situ toafford a carbodiimide that further undergoes a spontaneous cyclization.

The dehydration of a urea to afford an intermediate carbodiimide is alsodocumented in the literature (Appel, R., Kleinstuck, R., Ziehn, K. Chem.Ber. 1971, 104, 1335). However, the process of the present inventiongoes beyond the dehydration of the urea intermediate, since thecarbodiimide is not isolated and undergoes a spontaneous cyclization togive IIa.

Moreover, the novel compound of formula IIa is another aspect of thepresent invention and is not disclosed in the above cited references.

Suitable C₁₋₆alkyl R groups for the isocyanatoacetate and formula IIa instep a) include, for example, methyl and ethyl.

Step a) is performed in an aprotic organic solvent. Suitable aproticorganic solvents for this step include, for example, tetrahydrofuran,toluene, dichloromethane, dichloroethane and chloroform. Suitabletriarylphosphines in step a) include, for example, triphenylphosphine,wherein the phenyl groups are optionally substituted, for example, withone or more methoxy or amino groups. Suitable carbon tetrahalides instep a) include, for example, CCl₄ and CBr₄. Suitable tertiary amines instep a) include, for example, trialkylamine, 1-methylpyrrolidine or1-methylmorpholine. A preferred tertiary amine for use in step a) istriethylamine.

Step (b)

Step (b) of the inventive process is an optional hydrolysis step andcomprises hydrolyzing the ester compound of the formula IIa produced instep a) by reacting the compound of formula IIa with a base to form thecorresponding acid compound of the formula IIb:

Suitable bases for this step include, for example, alkali metalhydroxides such as lithium hydroxide, sodium hydroxide or potassiumhydroxide. The novel compound of formula IIb produced in this step isanother aspect of the present invention.

In one embodiment of the inventive process, this optional hydrolysisstep b) is not performed and the ester of formula IIa produced in stepa) is used directly in the next step of the process, step c).

Step (c)

Step (c) of the inventive process comprises reacting a compound of theformula IIa produced in step a) with a Lewis acid and a phosphine oxidecompound of the formula (R₁)₃PO, wherein R₁ is C₁₋₆alkyl or aryl, in anaprotic organic solvent to form a compound of the formula III:

or

when the optional step b) is performed, step c) comprises reacting acompound of the formula IIb produced in step b) with a coupling agent inan aprotic organic solvent to form a compound of the formula III:

When the ester compound of formula IIa is employed in step (c), theester IIa is cyclized in the presence of a Lewis acid and a phosphineoxide compound to provide the imidazo-imidazole-3,5-dione of formula IIIin good yield. This is similar to a known procedure for the synthesis oflactams (Takahata, H., Banba, Y., Momose, T. Tetrahedron, 1991, 47,7635). It was observed, however, that following the reaction conditionsdescribed in the literature failed to afford the desired product III insignificant yield. It was discovered that the addition of a phosphineoxide compound of the formula (R₁)₃PO, wherein R₁ is C₁₋₆alkyl or aryl,was necessary for the reaction to proceed efficiently.

Step c) is performed in an aprotic organic solvent. Suitable aproticorganic solvents for this step include, for example, tetrahydrofuran,toluene, dichloromethane, dichloroethane or chloroform. Suitable Lewisacids for use in this step include, for example, AlCl₃, TiCl₄ andtrialkylaluminums of the formula (C₁₋₆alkyl)₃Al, such as Me₃Al. Suitablephosphine oxides for this step include, for example, triarylphosphineoxides such as triphenylphosphine oxide, wherein the phenyl groups areoptionally substituted with one or more methoxy or amino groups.

When the acid compound of formula IIb is employed in step (c), acoupling agent is used to cause cyclization via an intramolecularcoupling between the carboxylic acid group and the amine group (i.e., apeptide-type coupling reaction). Suitable coupling agents for thispurpose include conventional peptide coupling agents, for example,acetic anhydride, acetyl chloride, thionyl chloride and oxalyl chloride.Suitable aprotic organic solvents for this step are the same asdescribed above.

The novel imidazo-imidazole-3,5-dione compound of formula III producedin step c) is another aspect of the present invention.

Step (d)

Step (d) of the inventive process comprises reacting a compound of theformula III produced in step c) with a strong base and a compound of theformula (R₂O)₂POCl, wherein R₂ is C₁₋₆alkyl or aryl, in a polar organicsolvent at a temperature of about −90° C. to about 0° C. to form acompound of the formula IV where R₂ is C₁₋₆alkyl or aryl:

The synthesis of the vinyl phosphate compound IV is similar to a knownprocedure for the preparation of ketene aminal phosphates from lactams(Nicolau, K. C., Shi, G., Kenji, N., Bemal, F. Chem. Commun. 1998,1757).

The novel vinyl phosphate compound of formula IV produced in step d) isanother aspect of the present invention and is not disclosed by theabove cited reference.

Step d) is conducted in the presence of a strong base. In the context ofthis invention, a strong base is a base having a pKa of greater than 20.Suitable strong bases for use in this step include, for example, alkalimetal amides, such as potassium bis(trimethylsilyl)amide, lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and lithiumdiisopropylamide.

In one embodiment, the R₂ group in the chlorophosphate compound(R₂O)₂POCl and in the compound of formula IV is a C₁₋₆alkyl group,preferably methyl or ethyl. Step d) is conducted in a polar organicsolvent. Suitable polar organic solvents include, for example, diethylether, dipropyl ether, diisopropyl ether, dibutyl ether, methyltert-butyl ether (MTBE), dipentyl ether, diisopentyl ether, ethyleneglycol dimethyl ether, diethylene glycol dimethyl ether, dioxane,tetrahydrofuran, N,N-dimethylformamide, N,N-dimethyl-acetamide, DMSO orN-methyl-2-pyrollidone.

Step d) is conducted at a temperature of about −90° C. to about 0° C.,preferably about −50° C. to about −5° C., more preferably about −30° C.to about −10° C. In one embodiment, step d) is conducted at atemperature of about −20° C. The term “about” in this context means atemperature between 10% above and 10% below the recited value,inclusive. For example, “about −20° C.” means a temperature falling inthe range −18° C. to −22° C.

Step (e)

Step (e) of the inventive process is an iodination that comprisesreacting a compound of the formula IV produced in step d) withtrimethylsilyl iodide (TMSI), or with sodium iodide (NaI) andtrimethylsilyl chloride (TMSCl), in an aprotic organic solvent to form acompound of the formula 1:

The synthesis of the compound of formula 1 from the vinyl phosphatecompound of formula IV is related to a known procedure for thepreparation of vinyl iodides from ketone-derived enol phosphates (Lee,K., Wiemer, D. F. Tetrahedron Lett. 1993, 34, 2433).

However, the enol phosphates in the literature procedure areketone-derived vinyl phosphates and not lactam-derived ketene aminalphosphates like formula IV.

The iodination in step e) is conducted by reacting the vinyl phosphatecompound of formula IV with trimethylsilyl iodide, or with sodium iodideand trimethylsilyl chloride. When sodium iodide and trimethylsilylchloride are used, these two compounds react in situ to formtrimethylsilyl iodide, which then reacts with formula IV to form theiodinated compound of formula 1.

Step e) is conducted in an aprotic organic solvent. Suitable aproticorganic solvents for this step include, for example, tetrahydrofuran,toluene, dichloromethane, dichloroethane, chloroform and acetonitrile.

Step (e) is optionally conducted in the presence of water. It has beenfound that water accelerates the formation of the iodide compound offormula 1. This step has been run with up to 6 equivalents of water,although higher amounts of water can be used. In one embodiment, theamount of water present is from about 0.5 to 1.5 equivalents, preferablyabout 0.8 to 1.2 equivalents.

SYNTHETIC EXAMPLES

The invention is further illustrated by the following non-limitingexamples of the inventive process.

EXAMPLE 1(R){3-[2-(4-Bromophenyl)-1-(3,5-dichlorophenylcarbamoyl)-1-methyl-ethyl]-ureido}-aceticAcid Ethyl Ester

Ethyl isocyanatoacetate (80.7 mL, 719 mmol) was added dropwise to astirred solution of I (281 g, 698 mmol) and THF (2 L) at ambienttemperature. The mixture was stirred at room temperature for 12 h andhexane (600 mL) was added. The resulting solid was collected byfiltration. The filtrate was concentrated under reduced pressure and theresulting precipitate was again collected by filtration. The solidmaterial was combined to afford a total of 325 g of product as a whitesolid: ¹H NMR (400 MHz, (D₃C)₂SO) δ1.17 (t, J=7.1 Hz, 3H), 1.23 (s, 3H),3.05 (d, J=13.3 Hz, 1H), 3.29 (d, J=13.3 Hz, 1H), 3.75 (dd, J=6.0 Hz,J=17.7 Hz, 1H), 3.84 (dd, J=6.0, J=17.7 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H),6.35 (s, 1H), 6.40 (t, J=6.0 Hz, 1H), 7.10 (d, J=8.2 Hz, 2H), 7.23(t,J=1.8 Hz, 1H), 7.44 (d, J=8.2 Hz, 2H), 7.74 (d, J=1.8 Hz, 2H), 9.83(s, 1H).

EXAMPLE 2(R)-[4-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-4-methyl-5-oxo-imidazolidin-2-ylideneamino]-aceticAcid Ethyl Ester

Method A:

Carbon tetrachloride (43.6 mL, 452 mmol) was added dropwise to a stirredsolution of the product of Example 1 (120 g, 226 mmol), triethylamine(63.0 mL, 452 mmol), triphenylphosphine (119 g, 452 mmol) anddichloromethane (1.8 L) at room temperature. The mixture was stirred atambient temperature for 12 h and concentrated under reduced pressure.Ethyl acetate (1.2 L) was added and the mixture was stirred for 5-10min. The solids were removed by filtration and the organic layer waswashed sequentially with 0.5 N HCl (450 mL) and saturated aqueous NaHCO₃(450 mL). The mixture was concentrated under reduced pressure to affordan orange oil. Ethyl acetate (240 mL) was added to the mixture at 50° C.followed by MTBE (720 mL) and the mixture was stirred at 60° C. for afew min. The mixture was allowed to reach ambient temperature and wasstirred for 12 h. The precipitate (triphenylphosphine oxide) was thenremoved by filtration and the filtrate was concentrated under reducedpressure to afford 134 g of an orange solid. ¹H NMR analysis of thecrude material indicated it contained about 38% w/w triphenylphosphineoxide. A small sample was purified by chromatography for analyticalpurposes and the bulk of the material was used for the next step withoutfurther purification.

Method B:

Ethyl isocyanatoacetate (0.287 mL, 2.56 mmol) was added dropwise to astirred solution of I (1.0 g, 2.49 mmol) and dichloromethane (5 mL) atroom temperature. The mixture was stirred for 10 min at room temperatureand the urea (product of Example 1) forms as a white precipitate.Stirring was continued for about 2 h thereafter to ensure completeconversion to the urea, and then triphenylphosphine (1.31 g, 4.98 mmol),triethylamine (0.69 mL, 4.98 mmol), and carbon tetrachloride (0.48 mL,4.98 mmol) were added to the stirred suspension. The mixture was thenstirred at ambient temperature for 12 h.

Aqueous workup (1 N HCl, dichloromethane, MgSO₄) afforded a yellow oil.Flash chromatography (silica gel, 4:1 hexane/ethyl acetate v/v) afforded906 mg (71%) of product as a white solid: mp 103-105° C.; ¹H NMR (400MHz, CDCl₃) δ1.31 (t, J=7.1 Hz, 3H), 1.52 (s, 3H), 2.95 (d, J=12.9 Hz,1H), 2.98 (d, J=12.9 Hz, 1H), 4.05-4.13 (m, 3H), 4.23 (m, 2H), 6.57 (d,J=1.6 Hz, 2H), 7.04 (d, J=8.2 Hz, 2H), 7.37 (m, 3H); ¹³C NMR (CDCl₃, 100MHz) δ14.1, 23.7, 42.9, 44.2, 61.7, 70.4, 120.9, 125.6, 129.4, 130.8,131.9, 133.2, 134.8, 136.1, 151.1, 169.6, 181.5; Anal. calcd forC₂₁H₂₀BrCl₂N₃O₃: C, 49.15; H, 3.93; N, 8.19. Found C, 49.46; H, 3.92; N,7.96.

EXAMPLE 3(R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-3-methyl-1,6-dihydroimidazo[1,2-a]imidazole-2,5-dione

Toluene (450 mL) was added to 76.9 g of a mixture of the product ofExample 2 (47.1 g, 91.7 mmol) and triphenylphosphine oxide (29.2 g, 105mmol), and the resulting solution was cooled down to −10° C.Trimethylaluminum (46 mL of a 2 M solution in toluene, 92 mmol) wasadded dropwise keeping the temperature at or below 0° C. and the mixturewas then allowed to reach ambient temperature. The mixture was stirredat ambient temperature for two h and more trimethylaluminum (27.6 mL ofa 2 M solution in toluene, 55.2 mmol) was added in two portions at two hintervals. The mixture was placed over an ice bath and slowly quenchedwith 1 N HCl (360 mL). The organic portion was separated and the aqueousportion was extracted with toluene (200 mL). The combined organicportions were washed with water and concentrated under reduced pressureto afford an orange oil. Flash chromatography (silica gel, hexane/ethylacetete 4:1 v/v) afforded 38.1 g (89%) of product as an oil thatsolidified upon standing: mp 52-54° C.; ¹H NMR (400 MHz, CDCl₃) δ1.84(s, 3H), 3.24 (d, J=13.8 Hz, 1H), 3.43 (d, J=13.8 Hz, 1H), 4.18 (d,J=21.9 Hz, 1H), 4.30 (d, J=21.9 Hz, 1H), 6.95 (d, J=8.3 Hz, 2 H), 7.29(d, J=1.8 Hz, 2H), 7.33 (t, J=1.8 Hz, 1H), 7.38 (d, J=8.3 Hz, 2H); ¹³CNMR (100 MHz, CDCl₃) δ21.5, 40.8, 61.3, 65.1, 122.3, 122.6, 128.5,131.0, 132.0, 132.5, 132.7, 135.5, 154.6, 174.3, 174.9; Anal. calcd forC₁₉H₁₄BrC₁₂N₃O₂: C, 48.85; H, 3.02; N, 9.00. Found C, 48.89; H, 3.02; N,8.81.

EXAMPLE 4 Phosphoric acid (R)5-(4-bromobenzyl)-7-(3,5-dichlorophenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazol-3-ylEster Diethyl Ester

Potassium bis(trimethylsilyl)amide (265 mL of a 0.5 M solution intoluene, 133 mmol) was added dropwise to a stirred solution of theproduct of Example 3 (51.5 g, 110.3 mmol), diethyl chlorophosphate (23.9mL, 165 mmol) and THF (700 ml) at −20° C. The mixture was stirred at−20° C. for one h. Aqueous workup (aqueous NH₄Cl, ethyl acetate, MgSO₄)afforded an oil. Flash chromatography (silica gel, hexane/ethyl acetate2:1 v/v) afforded 61.2 g (92%) of product as a yellow oil: ¹H NMR (400MHz, CDC1₃) δ1.44 (t, J=7.1 Hz, 6H), 1.86 (s, 3H), 3.26 (d, J=13.9 Hz),3.34 (d, J=13.9 Hz, 1H), 4.33 (m, 4 H), 6.50 (s, 1H), 6.84 (d, J=8.2 Hz,2H), 7.24-7.28 (m, 3H), 7.58 (d, J=1.6 Hz, 2H).

EXAMPLE 5(R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-5-iodo-3-methyl-1H-imidazo[1,2-a]imidazol-2-one

Trimethylsilyl chloride (42.8 mL, 338 mmol) was added dropwise to astirred suspension of Nal (49.5 g, 330 mmol), the product of Example 4(66.3 g, 110 mmol) and dichloromethane (1.1 L) at −10° C. The mixturewas allowed to reach ambient temperature and stirred for 90 min. Themixture was placed over an ice bath and quenched with a mixture ofsaturated aqueous NaHCO₃ solution (360 mL) and 10% aqueous sodiumthiosulfate (360 mL). The organic layer was set aside and the aqueouslayer was extracted with dichloromethane (500 mL). The combined organicportions were dried (MgSO₄) and concentrated to afford 100 g of a lightbrown oil. Flash chromatography (silica gel, 6:1 hexane/ethyl acetatev/v) afforded 44.1 g (69%) of product as a colorless solid: ¹H NMR (400MHz, CDCl₃) δ1.92 (s, 3H), 3.24 (d, J=14 Hz, 1H), 3.54 (d, J=14 Hz, 1H), 6.78 (d, J=8.3 Hz, 2H), 6.95 (s, 1H), 7.27 (m, 3H), 7.53 (d, J=1.8Hz, 2H).

What is claimed is:
 1. A compound having the following formula IV:

wherein R₂ is C₁₋₆alkyl or aryl.
 2. A process for preparing a compoundof claim 1 having the formula IV, said process comprising reacting acompound of the formula III with a strong base, a compound of theformula (R₂O)₂POCl, wherein R₂ is C₁₋₆alkyl or aryl, in a polar organicsolvent at a temperature of about −90° C. to about 0° C. to form acompound of the formula IV where R₂ is C₁₋₆alkyl or aryl: